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Endometriosis – What is it?

Endometriosis is a gynecological medical condition in which cells from the lining of the uterus (endometrium) appear and flourish outside the uterine cavity, most commonly on the membrane which lines the abdominal cavity. The uterine cavity is lined with endometrial cells, which are under the influence of female hormones. Endometrial-like cells in areas outside the uterus (endometriosis) are influenced by hormonal changes and respond in a way that is similar to the cells found inside the uterus. Symptoms often worsen with the menstrual cycle.

Endometriosis is typically seen during the reproductive years; it has been estimated that endometriosis occurs in roughly 6–10% of women.[1]Symptoms may depend on the site of active endometriosis. Its main but not universal symptom is pelvic pain in various manifestations. Endometriosis is a common finding in women with infertility.[1]

There is no cure for endometriosis, but it can be treated in a variety of ways, including pain medication, hormonal treatments, and surgery

Signs and symptoms

Pelvic pain

A major symptom of endometriosis is recurring pelvic pain. The pain can range from mild to severe cramping that occurs on both sides of the pelvis, in the lower back and rectal area, and even down the legs. The amount of pain a woman feels correlates poorly with the extent or stage (1 through 4) of endometriosis, with some women having little or no pain despite having extensive endometriosis or endometriosis with scarring, while other women may have severe pain even though they have only a few small areas of endometriosis.[3] Symptoms of endometriosis-related pain may include:[4]

dysmenorrhea – painful, sometimes disabling cramps during menses; pain may get worse over time (progressive pain), also lower back pains linked to the pelvis

Throbbing, gnawing, and dragging pain to the legs are reported more commonly by women with endometriosis.[5] Compared with women with superficial endometriosis, those with deep disease appear to be more likely to report shooting rectal pain and a sense of their insides being pulled down.[citation needed] Individual pain areas and pain intensity appears to be unrelated to the surgical diagnosis, and the area of pain unrelated to area of endometriosis.[citation needed]

Endometriosis lesions react to hormonal stimulation and may “bleed” at the time of menstruation. The blood accumulates locally, causes swelling, and triggers inflammatory responses with the activation of cytokines. This process may cause pain. Pain can also occur from adhesions (internal scar tissue) binding internal organs to each other, causing organ dislocation. Fallopian tubes, ovaries, the uterus, the bowels, and the bladder can be bound together in ways that are painful on a daily basis, not just during menstrual periods.[citation needed]

Also, endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the central nervous system, potentially producing a variety of individual differences in pain that can, in some women, become independent of the disease itself.[3]

Fertility

Many women with infertility may have endometriosis. As endometriosis can lead to anatomical distortions and adhesions (the fibrous bands that form between tissues and organs following recovery from an injury), the causality may be easy to understand; however, the link between infertility and endometriosis remains enigmatic when the extent of endometriosis is limited.[6] It has been suggested that endometriotic lesions release factors which are detrimental to gametes or embryos, or, alternatively, endometriosis may more likely develop in women who fail to conceive for other reasons and thus be a secondary phenomenon; for this reason it is preferable to speak of endometriosis-associated infertility.[7]

Other

In addition to pain during menstruation, the pain of endometriosis can occur at other times of the month. There can be pain with ovulation, pain associated with adhesions, pain caused by inflammation in the pelvic cavity, pain during bowel movements and urination, during general bodily movement like exercise, pain from standing or walking, and pain with intercourse. But the most desperate pain is usually with menstruation and many women dread having their periods. Pain can also start a week before menses, during and even a week after menses, or it can be constant. There is no known cure for endometriosis.[9]

Complications

Complications of endometriosis include internal scarring, adhesions, pelvic cysts, chocolate cyst of ovaries, ruptured cysts, and bowel and ureteral obstruction resulting from pelvic adhesions.[citation needed] Infertility can be related to scar formation and anatomical distortions due to the endometriosis; however, endometriosis may also interfere in more subtle ways: cytokines and other chemical agents may be released that interfere with reproduction.[citation needed]Peritonitis from bowel perforation can occur.[citation needed]

Risk factors

Environmental toxins

Several studies have investigated the potential link between exposure to dioxins and endometriosis, but the evidence is equivocal and potential mechanisms are poorly understood.[15] In the early 1990s, Sherry Rier and colleagues found that 79% of a group of monkeys developed endometriosis ten years after exposure to dioxin. The severity of endometriosis found in the monkeys was directly related to the amount of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin – the most toxic dioxin) to which they had been exposed . Monkeys that were fed dioxin in amounts as small as five parts per trillion developed endometriosis. In addition, the dioxin-exposed monkeys showed immune abnormalities similar to those observed in women with endometriosis.[16] A similar follow up study in 2000 observed similar findings.[17] However, a 2004 review of studies of dioxin and endometriosis concluded that “the human data supporting the dioxin-endometriosis association are scanty and conflicting,”[18] and in 2009, another literature review by the same author found that there was “insufficient evidence at this moment” in support of a link between dioxin exposure and women developing endometriosis.[19] A 2008 review by Rier, however, concluded that more work was needed, stating that “although preliminary work suggests a potential involvement of exposure to dioxins in the pathogenesis of endometriosis, much work remains to clearly define cause and effect and to understand the potential mechanism of toxicity.”[20]

Genetics

Genetic predisposition plays a role in endometriosis.[21] Daughters or sisters of patients with endometriosis are at higher risk of developing endometriosis themselves; low progesterone levels may be genetic, and may contribute to a hormone imbalance.[22] There is an about 6-fold increased incidence in women with an affected first-degree relative.[23]

It has been proposed that endometriosis results from a series of multiple hits within target genes, in a mechanism similar to the development of cancer.[21] In this case, the initial mutation may be either somatic or heritable.[21]

Individual genomic changes (found by genotyping) that have been associated with endometriosis include:

In addition, there are many findings of altered gene expression and epigenetics, but both of these can also be a secondary result of, for example, environmental factors and altered metabolism. Examples of altered gene expression include that of miRNAs.[21]

Aging

Aging brings with it many effects that may reduce fertility. Depletion over time of ovarian follicles affects menstrual regularity. Endometriosis has more time to produce scarring of the ovary and tubes so they cannot move freely or it can even replace ovarian follicular tissue if ovarian endometriosis persists and grows. Leiomyomata (fibroids) can slowly grow and start causing endometrial bleeding that disrupts implantation sites or distorts the endometrial cavity which affects carrying a pregnancy in the very early stages. Abdominal adhesions from other intraabdominal surgery, or ruptured ovarian cysts can also affect tubal motility needed to sweep the ovary and gather an ovulated follicle (egg).

Incidences of endometriosis have occurred in postmenopausal women,[26] and in less common cases, girls may have endometriosis symptoms before they even reach menarche.[27][28]

Pathophysiology

While the exact cause of endometriosis remains unknown, many theories have been presented to better understand and explain its development. These concepts do not necessarily exclude each other. The pathophysiology of endometriosis is likely to be multifactorial and to involve an interplay between several factors.[21]

Broadly, the aspects of the pathophysiology can basically be classified as underlying predisposing factors, metabolic changes, formation of ectopic endometrium, and generation of pain and other effects. It is not certain, however, to what degree predisposing factors lead to metabolic changes and so on, or if metabolic changes or formation of ectopic endometrium is the primary cause. Also, there are several theories within each category, but the uncertainty over what is a cause versus what is an effect when considered in relation to other aspects is as true for any individual entry in the pathophysiology of endometriosis.[21]

Also, pathogenic mechanisms appear to differ in the formation of distinct types of endometriotic lesion, such as peritoneal, ovarian and rectovaginal lesions.[21]

Formation of ectopic endometrium

The main theories for the formation of ectopic endometrium are retrograde menstruation, müllerianosis, coelomic metaplasia and transplantation, each further described below.

Retrograde menstruation

The theory of retrograde menstruation (also called the implantation theory or transplantation theory)[29] is the most widely accepted theory for the formation of ectopic endometrium in endometriosis.[21] It suggests that during a woman’s menstrual flow, some of the endometrial debris exits the uterus through the fallopian tubes and attaches itself to the peritoneal surface (the lining of the abdominal cavity) where it can proceed to invade the tissue as endometriosis.[21]

While most women may have some retrograde menstrual flow, typically their immune system is able to clear the debris and prevent implantation and growth of cells from this occurrence. However, in some patients, endometrial tissue transplanted by retrograde menstruation may be able to implant and establish itself as endometriosis. Factors that might cause the tissue to grow in some women but not in others need to be studied, and some of the possible causes below may provide some explanation, e.g., hereditary factors, toxins, or a compromised immune system. It can be argued that the uninterrupted occurrence of regular menstruation month after month for decades is a modern phenomenon, as in the past women had more frequent menstrual rest due to pregnancy and lactation.

Retrograde menstruation alone is not able to explain all instances of endometriosis, and it needs additional factors such as genetic or immune differences to account for the fact that many women with retrograde menstruation do not have endometriosis. Research is focusing on the possibility that the immune system may not be able to cope with the cyclic onslaught of retrograde menstrual fluid. In this context there is interest in studying the relationship of endometriosis to autoimmune disease, allergic reactions, and the impact of toxins.[30][31] It is still unclear what, if any, causal relationship exists between toxins, autoimmune disease, and endometriosis

In addition, at least one study found that endometriotic lesions are biochemically very different from artificially transplanted ectopic tissue.[32] The latter finding, however, can in turn be explained by that the cells that establish endometrial lesions are not of the main cell type in ordinary endometrium, but rather of a side population cell type, as supported by exhibitition of a side population phenotype upon staining with Hoechst dye and by flow cytometric analysis.[21]

In rare cases where imperforate hymen does not resolve itself prior to the first menstrual cycle and goes undetected, blood and endometrium are trapped within the uterus of the patient until such time as the problem is resolved by surgical incision. Many health care practitioners never encounter this defect, and due to the flu-like symptoms it is often misdiagnosed or overlooked until multiple menstrual cycles have passed. By the time a correct diagnosis has been made, endometrium and other fluids have filled the uterus and fallopian tubes with results similar to retrograde menstruation resulting in endometriosis. The initial stage of endometriosis may vary based on the time elapsed between onset and surgical procedure.

The theory of retrograde menstruation as a cause of endometriosis was first proposed by John A. Sampson.

Other theories of endometrial formation

Müllerianosis: A competing theory states that cells with the potential to become endometrial are laid down in tracts during embryonic development and organogenesis. These tracts follow the female reproductive (Mullerian) tract as it migrates caudally (downward) at 8–10 weeks of embryonic life. Primitive endometrial cells become dislocated from the migrating uterus and act like seeds or stem cells. This theory is supported by foetal autopsy.[33]

Coelomic metaplasia: This theory is based on the fact that coelomicepithelium is the common ancestor of endometrial and peritoneal cells and hypothesizes that later metaplasia(transformation) from one type of cell to the other is possible, perhaps triggered by inflammation.[34]

Less commonly lesions can be found on the diaphragm. Diaphragmatic endometriosis is rare, almost always on the right hemidiaphragm, and may inflict cyclic pain of the right shoulder just before and during menses. Rarely, endometriosis can be extraperitoneal and is found in the lungs and CNS.[36]

Diagnosis

A health history and a physical examination can in many patients lead the physician to suspect endometriosis. Laparoscopy, a surgical procedure where a camera is used to look inside the abdominal cavity, is the gold standard in diagnosis. However, in the United States most insurance plans will not cover surgical diagnosis unless the patient has already attempted to become pregnant and failed.

Use of imaging tests may identify endometriotic cysts or larger endometriotic areas. It also may identify free fluid often within the Recto-uterine pouch. The two most common imaging tests are ultrasound and magnetic resonance imaging (MRI). Normal results on these tests do not eliminate the possibility of endometriosis. Areas of endometriosis are often too small to be seen by these tests.

The only way to diagnose endometriosis is by laparoscopy or other types of surgery with lesion biopsy.[citation needed] The diagnosis is based on the characteristic appearance of the disease, and should be corroborated by a biopsy. Surgery for diagnoses also allows for surgical treatment of endometriosis at the same time.

Although doctors can often feel the endometrial growths during a pelvic exam, and these symptoms may be signs of endometriosis, diagnosis cannot be confirmed without performing a laparoscopic procedure. To the eye, lesions can appear dark blue, powder-burn black, red, white, yellow, brown or non-pigmented. Lesions vary in size. Some within the pelvis walls may not be visible, as normal-appearing peritoneum of infertile women reveals endometriosis on biopsy in 6–13% of cases.[37] Early endometriosis typically occurs on the surfaces of organs in the pelvic and intra-abdominal areas. Health care providers may call areas of endometriosis by different names, such as implants, lesions, or nodules. Larger lesions may be seen within the ovaries as ovarian endometriomas or “chocolate cysts”, “chocolate” because they contain a thick brownish fluid, mostly old blood.

Often the symptoms of ovarian cancer are identical to those of endometriosis.[citation needed]

If surgery is not performed, then a diagnosis of exclusion process is used. This means that all of the other plausible causes of pelvic pain are ruled out. For example, internal hernias are difficult to identify in women, and misdiagnosis with endometriosis is very common. One cause of misdiagnosis is that when the woman lies down flat on an examination table, all of the medical signs of the hernia disappear, but the woman typically has tenderness and other symptoms associated with endometriosis in a pelvic exam. The hernia can typically only be detected when symptoms are present, so diagnosis requires positioning the woman’s body in a way that provokes symptoms.[unreliable medical source?][38]

Staging

Surgically, endometriosis can be staged I–IV (Revised Classification of the American Society of Reproductive Medicine).[39] The process is a complex point system that assesses lesions and adhesions in the pelvic organs, but it is important to note staging assesses physical disease only, not the level of pain or infertility. A patient with Stage I endometriosis may have little disease and severe pain, while a patient with Stage IV endometriosis may have severe disease and no pain or vice versa. In principle the various stages show these findings:

Stage I (Minimal)

Findings restricted to only superficial lesions and possibly a few filmy adhesions

As above, plus presence of endometriomas on the ovary and more adhesions.

Stage IV (Severe)

As above, plus large endometriomas, extensive adhesions.

Endometrioma on the ovary of any significant size (Approx. 2 cm +) must be removed surgically because hormonal treatment alone will not remove the full endometrioma cyst, which can progress to acute pain from the rupturing of the cyst and internal bleeding. Endometrioma is sometimes misdiagnosed as ovarian cysts.

Markers

A systematic review in 2010 of essentially all proposed biomarkers for endometriosis in serum, plasma and urine came to the conclusion that none of them have been clearly shown to be of clinical use, although some appear to be promising.[40] Another review in 2011 identified several putative biomarkers upon biopsy, including findings of small sensory nerve fibers or defectively expressed β3 integrin subunit.[41]

The one biomarker that has been used in clinical practice over the last 20 years is CA-125.[40] However, its performance in diagnosing endometriosis is low, even though it shows some promise in detecting more severe disease.[40] CA-125 levels appear to fall during endometriosis treatment, but has not shown a correlation with disease response.[40]

It has been postulated a future diagnostic tool for endometriosis will consist of a panel of several biomarkers, including both substance concentrations and genetic predisposition.[40]

Management

While there is no cure for endometriosis, in many women menopause (natural or surgical) will abate the process. In patients in the reproductive years, endometriosis is merely managed: the goal is to provide pain relief, to restrict progression of the process, and to restore or preserve fertility where needed. In younger women with unfulfilled reproductive potential, surgical treatment attempts to remove endometrial tissue and preserving the ovaries without damaging normal tissue.

In general, the diagnosis of endometriosis is confirmed during surgery, at which time ablative steps can be taken. Further steps depend on circumstances: patients without infertility can be managed with hormonal medication that suppress the natural cycle and pain medication, while infertile patients may be treated expectantly after surgery, with fertility medication, or with IVF.

Sonography is a method to monitor recurrence of endometriomas during treatments.

Treatments for endometriosis in women who do not wish to become pregnant include:

Hormonal medication

Progesterone or Progestins: Progesterone counteracts estrogen and inhibits the growth of the endometrium. Such therapy can reduce or eliminate menstruation in a controlled and reversible fashion. Progestins are chemical variants of natural progesterone.

Avoiding products with xenoestrogens, which have a similar effect to naturally produced estrogen and can increase growth of the endometrium.

Hormone contraception therapy: Oral contraceptives reduce the menstrual pain associated with endometriosis.[43] They may function by reducing or eliminating menstrual flow and providing estrogen support. Typically, it is a long-term approach. Recently Seasonale was FDA approved to reduce periods to 4 per year. Other OCPs have however been used like this off label for years. Continuous hormonal contraception consists of the use of combined oral contraceptive pills without the use of placebo pills, or the use of NuvaRing or the contraceptive patch without the break week. This eliminates monthly bleeding episodes.

Danazol (Danocrine) and gestrinone are suppressive steroids with some androgenic activity. Both agents inhibit the growth of endometriosis but their use remains limited as they may causehirsutism and voice changes.

Gonadotropin Releasing Hormone (GnRH) agonist: These agents work by increasing the levels of GnRH. Consistent stimulation of the GnRH receptors results in downregulation, inducing a profound hypoestrogenism by decreasing FSH and LH levels. While effective in some patients, they induce unpleasant menopausal symptoms, and over time may lead to osteoporosis. To counteract such side effects some estrogen may have to be given back (add-back therapy). These drugs can only be used for six months at a time.

Lupron depo shot is a GnRH agonist and is used to lower the hormone levels in the woman’s body to prevent or reduce growth of endometriosis. The injection is given in 2 different doses: a 3 month course of monthly injections, each with the dosage of (11.25 mg); or a 6 month course of monthly injections, each with the dosage of (3.75 mg).[citation needed]

Aromatase inhibitors are medications that block the formation of estrogen and have become of interest for researchers who are treating endometriosis.[44]

Other medication

NSAIDs: Anti-inflammatory. They are commonly used in conjunction with other therapy. For more severe cases narcotic prescription drugs may be used. NSAID injections can be helpful for severe pain or if stomach pain prevents oral NSAID use.

Opioids: Morphine sulphate tablets and other opioid painkillers work by mimicking the action of naturally occurring pain-reducing chemicals called “endorphins“. There are different long acting and short acting medications that can be used alone or in combination to provide appropriate pain control.

Following laparoscopic surgery women who were given Chinese herbs were reported to have comparable benefits to women with conventional drug treatments, though the journal article that reviewed this study also noted that “the two trials included in this review are of poor methodological quality so these findings must be interpreted cautiously. Better quality randomised controlled trials are needed to investigate a possible role for CHM [Chinese Herbal Medicine] in the treatment of endometriosis.”,[45]

Pentoxifylline, a phosphodiesterase inhibitor, has a proposed action of inhibiting the production of inflammatory cytokines as well as inhibiting the activation of immune cells in peritoneal fluid, thereby decreasing pain from endometriosis and improving fertility. On systematic review by the Cochrane Collaboration, randomized controlled trials have shown a trend towards improving pregnancy rates with pentoxifylline treatment (odds ratio of 1.54, 95% CI 0.89-2.66) and a decreasing trend in pain scores with treatment (mean difference -1.60, 95% CI -3.32-0.12). However, neither of these outcomes reached statistical significance on analysis.[46] Current American Congress of Obstetricians and Gynecologists (ACOG) guidelines do not include immune-modulators, such as pentoxifylline, in standard treatment protocols.[47]

Surgery

Procedures are classified as

conservative when reproductive organs are retained,

semi-conservative when ovarian function is allowed to continue,

Conservative therapy consists of the excision (called cystectomy) of the endometrium, adhesions, resection of endometriomas, and restoration of normal pelvic anatomy as much as is possible.[6]Laparoscopy, besides being used for diagnosis, can also be an option for surgery. It’s considered a “minimally invasive” surgery because the surgeon makes very small openings (incisions) at (or around) the belly button and lower portion of the belly. A thin telescope-like instrument (the laparoscope) is placed into one incision, which allows the doctor to look for endometriosis using a small camera attached to the laparoscope. Small instruments are inserted through the incisions to remove the tissue and adhesions. Because the incisions are very small, there will only be small scars on the skin after the procedure.[49]

Semi-conservative therapy preserves a healthy appearing ovary, but also increases the risk of recurrence.[50]

For patients with extreme pain, a presacral neurectomy may be indicated where the nerves to the uterus are cut. However, strong clinical evidence showed that presacral neurectomy is more effective in pain relief if the pelvic pain is midline concentrated, and not as effective if the pain extends to the left and right lower quadrants of the abdomen.[6] This is because the nerves to be transected in the procedure are innervating the central or the midline region in the female pelvis. Furthermore, women who had presacral neurectomy have higher prevalence of chronic constipation not responding well to medication treatment because of the potential injury to the parasympathetic nerve in the vicinity during the procedure.

After surgical treatment of deeply infiltrating endometriosis with colorectal involvement, the endometriosis recurrence rate is estimated to be 10% (ranging between 5 and 25%).[51]

Comparison of medicinal and surgical interventions

Efficacy studies show that both medicinal and surgical interventions produce roughly equivalent pain-relief benefits. Recurrence of pain was found to be 44 and 53 percent with medicinal and surgical interventions, respectively.[22] Each approach has advantages and disadvantages.[34]

The advantages of medicinal intervention are decreased initial cost, therapy can be modified as needed, and effective pain control.[citation needed] Its disadvantages are common adverse effects, unlikely improvement in fertility, and limitations on the length of time some can be used.[citation needed]

The advantages of surgery are demonstrated efficacy for pain control,[52] it is more effective for infertility than medicinal intervention,[citation needed] it provides a definitive diagnosis,[citation needed]and surgery can often be performed as a minimally invasive (laparoscopic) procedure to reduce morbidity and minimize the risk of post-operative adhesions.[53]

Treatment of infertility

While roughly similar to medicinal interventions in treating pain, the efficacy of surgery is especially significant in treating infertility. One study has shown that surgical treatment of endometriosis approximately doubles the fecundity (pregnancy rate).[54] The use of medical suppression after surgery for minimal/mild endometriosis has not shown benefits for patients with infertility.[7] Use of fertility medication that stimulates ovulation (clomiphene citrate, gonadotropins) combined with intrauterine insemination (IUI) enhances fertility in these patients.[7]

In-vitro fertilization (IVF) procedures are effective in improving fertility in many women with endometriosis. IVF makes it possible to combine sperm and eggs in a laboratory and then place the resulting embryos into the woman’s uterus. The decision when to apply IVF in endometriosis-associated infertility takes into account the age of the patient, the severity of the endometriosis, the presence of other infertility factors, and the results and duration of past treatments.

Prognosis

Proper counseling of patients with endometriosis requires attention to several aspects of the disorder. Of primary importance is the initial operative staging of the disease to obtain adequate information on which to base future decisions about therapy. The patient’s symptoms and desire for childbearing dictate appropriate therapy. Not all therapy works for all patients. Some patients have recurrences after surgery or pseudo-menopause. In most cases, treatment will give patients significant relief from pelvic pain and assist them in achieving pregnancy.[55]

The underlying process that causes endometriosis may not cease after surgical or medical intervention. Studies have shown that endometriosis recurs at a rate of 20 to 40 percent within five years following conservative surgery,[56] unless hysterectomy is performed or menopause reached. Monitoring of patients consists of periodic clinical examinations and sonography.

Vaginal childbirth decreases recurrence of endometriosis. In contrast, endometriosis recurrence rates have been shown to be higher in women who have not given birth vaginally, such as in Cesarean section.[57]

Epidemiology

Endometriosis can affect any female, from premenarche to postmenopause, regardless of race or ethnicity or whether or not they have had children. It is primarily a disease of the reproductive years.[58] Its prevalence varies, but 6–10% is a reasonable number, more common in women with infertility and chronic pelvic pain (35–50%).[1]